J. Phys. Chem. A 2010, 114, 8331–8336
8331
Mechanistic Insights into Cu(I)-Catalyzed Azide-Alkyne “Click” Cycloaddition Monitored
by Real Time Infrared Spectroscopy
Shengtong Sun and Peiyi Wu*
The Key Laboratory of Molecular Engineering of Polymers, Ministry of Education, Department of
Macromolecular Science, and Laboratory of AdVanced Materials, Fudan UniVersity, Shanghai 200433,
People’s Republic of China
ReceiVed: June 1, 2010; ReVised Manuscript ReceiVed: July 14, 2010
A designed ligand-accelerated Cu(I)-catalyzed cycloaddition (CuAAC) reaction was monitored for the first
time by real time infrared analysis technique based on ATR-FTIR principles. Principal components analysis
(PCA) and two-dimensional correlation spectroscopy (2Dcos) results showed that the consumption of alkyne
and azide took place successively followed by the formation of the product 1,2,3-triazole, and a 1:1 complex
of two reactants would be formed in the reaction process. The rate-determining step of the CuAAC reaction
was also experimentally confirmed for the first time to be the transition of azide-alkyne 1:1 complex to the
preproduct 1,2,3-triazole. Our results are in good conformity with the current catalytic mechanism proposed
by Sharpless et al. according to DFT calculation results.
1. Introduction
As natural molecules have an overall preference for
carbon-heteroatom bonds, in contrary to our focus on organic
synthesis by carbon-carbon bonding nowadays, click chemistry
serves as a rather powerful strategy in request for function with
highly energetic “spring-loaded” reactants.1 Of all the reactions
in the scope of click reaction, Cu(I)-catalyzed Huisgen 1,3dipolar azide-alkyne cycloaddition to yield 1,4-regioselective
1,2,3-triazoles2 is undoubtedly the most powerful and representative one discovered to date. This reaction can succeed with
high yields, purity, and reaction rate (up to 107 times) over a
broad temperature range (0-160 °C) and pH range (ca. 4-12)
and in the presence of the majority of organic synthesis
conditions and functional groups.3 In other words, Cu(I)catalyzed azide-alkyne cycloaddition (CuAAC) is a very robust
reaction which has opened growing applications in bioconjunction, organic synthesis, materials and surface science, polymer
science, etc.4
In spite of increasing studies on the applicability of CuAAC,
deep mechanistic understanding of the overall features of this
unique catalytic process appears much more difficult, due to
its “incredible” and “perfect” selectivity, reactivity, and reliability, which mainly involve multiple on- and off-cycle
equilibria, formation of ill-defined and catalytically incompetent
copper acetylide aggregates. Several investigations devoted to
comprehend the mechanism of CuAAC have been reported
recently by performing kinetics studies either for ligand-free5
or for ligand-accelerated6 CuAAC reactions, and some of its
derivative reactions such as cyclodimerization7 and Cu(I)catalyzed click step-growth polymerization8 are also very helpful
to achieve a better understanding of CuAAC. It is worth noting
that nearly all of the current mechanistic interpretations are based
on the results proposed by Sharpless et al., who predicted
unprecedented reactivity and intermediates of CuAAC via a DFT
study.9 Compared to the thermally induced Huisgen 1,3-dipolar
cycloaddition with a confirmed uncatalyzed concerted mechanism, CuAAC would adopt a stepwise annealing pathway to
* Corresponding author. E-mail: [email protected].
afford regioselective 1,4-substituted 1,2,3-triazoles. However,
concerted direct pathway cannot explain Cu(I)-catalyzed accelerating effect due to a too high barrier. Thus, two intermediates with much lower barriers were proposed to account for
this problem. Nevertheless, there is still no experimental proof
for its key steps and intermediates.
Herein, we report our mechanistic results from monitoring a
designed ligand-accelerated CuAAC reaction for the first time
by real time infrared analysis technique based on ATR-FTIR
principles. Unlike other online techniques, such as LC-MS,5,6b
NMR,8 or UV-vis10 with inextricable time delay, operation
inconvenience, and, mostly important, lack of direct response
to all reacting species, IR spectroscopy is very suitable for real
time monitoring of various chemical processes such as catalysis,
crystallization, organic/inorganic chemistry, pharmaceutical/
biological analysis, polymerization, etc.11 In this paper, two
powerful qualitative methods, chemometrics12 and two-dimensional correlation spectroscopy (2Dcos),13 were also used to
extract primary spectral information in order to experimentally
evaluate the rationality of the current mechanism by discerning
the sequence order of different reaction species and searching
for possible intermediates.
2. Experimental Section
2.1. Materials. Sodium azide (NaN3), propargyl alcohol, and
copper bromide (CuBr) were purchased from Aladdin Co. Ltd.,
and CuBr was purified by washing several times with methanol.
N,N,N′,N′,N′′-Pentamethyldiethylenetriamine (PMDETA, 98%)
was obtained from J&K Chemical Ltd. and used as received.
Benzyl bromide, acetic acid, and dimethylformamide (DMF)
were all purchased from Sinopharm Chemical Reagent Co. Ltd.,
and only DMF was purified by vacuum distillation before use.
Unless stated otherwise, other reagents and solvents were all
purchased from commercial suppliers and were used without
further purification.
2.2. Instruments and Measurements. Time-resolved online
ATR-FTIR spectra were recorded on a ReactIR 45 m spectrometer (Mettler-Toledo) equipped with a silicon probe with a
resolution of 8 cm-1 and 32 scans. After the probe was fixed
10.1021/jp105034m  2010 American Chemical Society
Published on Web 07/26/2010
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J. Phys. Chem. A, Vol. 114, No. 32, 2010
and all of the reactants were added, each spectrum was collected
immediately at intervals of 1 min under the protection of
nitrogen. An even agitation should be maintained to avoid
bringing bubbles onto the surface of the probe, which would
lead to a large intensity decrease of IR spectra. FTIR spectra of
pure components were measured on a Nicolet Nexus 470
spectrometer with a resolution of 4 cm-1 and 64 scans. 1H and
13
C NMR spectra were recorded on Varian Mercury plus 400
M spectrometer with CDCl3 as solvent and TMS as the internal
reference. Elemental analysis was performed on VARIO EL3
instrument (ELEMEN TAR, Germany). The melting point (mp)
was measured on a Mettler-Toledo differential scanning calorimeter thermal analyzer at a heating rate of 10 °C/min from 0
to 70 °C.
2.3. Synthesis Procedure. 2.3.1. Synthesis of Benzyl Azide
1 and Propargyl Acetate 2. Benzyl azide was synthesized as
described previously.8 The mixture of benzyl bromide (8.77 g,
0.051 mol) and sodium azide (10 g, 0.154 mol) in 50 mL of
DMF was stirred in the dark for 20 h at room temperature. After
filtration of NaBr and NaN3 salts and addition of 50 mL of water,
the product was extracted with diethyl ether (3 × 25 mL). Then
the solution was dried with anhydrous Na2SO4 overnight, and
concentrated residue was further purified by column chromatography with diethyl ether as the eluting solvent to afford 1 as
a colorless liquid (4.72 g, 70%). 1H NMR (CDCl3): δ 7.36 (m,
5H, C6H5-), δ 4.35 (s, 2H, -CH2-). 13C NMR (CDCl3): δ
135.6, 129.1, 128.6, 128.5, 55.0. IR: 2100 cm-1 (-N3).
2.3.2. Synthesis of Propargyl Acetate 2. The mixture of
propargyl alcohol (25 mL, 0.424 mol) and acetic acid (26 mL,
0.455 mol) was stirred vigorously overnight at room temperature
after adding 7-8 drops of concentrated H2SO4. Then 100 mL
of 5% Na2CO3 aqueous solution was added, and the product
was extracted by dichloromethane (3 × 50 mL), washed to
neutral with water. After drying with anhydrous Na2SO4
overnight, the solvent was removed to afford 2 as a colorless
liquid (9.7 g). 1H NMR (CDCl3): δ 4.68 (d, 2H, -CH2-), 2.53
(t, 1H, tC-H), 2.11 (s, 3H, -CH3). 13C NMR (CDCl3): δ
170.3, 77.8, 75.1, 20.9. IR: 3300 cm-1 (tC-H), 2135 cm-1
(CtC).
2.3.3. General Procedure for Cu(I)-Catalyzed Synthesis of
1,4-Disubstituted 1,2,3-Triazole 3. For [azide]/[alkyne] ) 1/1,
benzyl azide 1 (0.5 g, 3.76 mmol), CuBr (0.0108 g, 0.075
mmol), and PMDETA (31 µL, 0.15 mmol) were mixed in 10
mL of DMF first, and then propargyl acetate 2 (0.368 g, 3.76
mmol) was added into the solution. The Cu(I)-catalyzed
cycloaddition reaction proceeded at room temperature (20 °C)
under nitrogen protection for ca. 40 min and was real time
monitored by ReactIR throughout the process. After the reaction
finished, the reaction solution was diluted by a spot of DMF
and passed through a short alumina column to remove the
catalyst. After adding 20 mL of water to dissolve the solution,
the product was extracted with diethyl ether (3 × 25 mL) and
dried with anhydrous Na2SO4 overnight. To obtain the pure
product for spectral comparison, concentrated residue was
purified by column chromatography with diethyl ether as the
eluting solvent. After further recrystallization twice, a white
crystalline solid 3 (0.68 g, 78%) was obtained: mp 58-59 °C.
1
H NMR (CDCl3): δ 7.51 (s, 1H, H in triazole), 7.40-7.36 (m,
3H, m, p-H in C6H5-), 7.29-7.27 (m, 2H, o-H in C6H5-), 5.52
(s, 2H, -CH2- close to phenyl), 5.18 (s, 2H, -CH2- close to
ester), 2.05 (s, 3H, -CH3). 13C NMR (CDCl3): δ 171.1, 143.6,
134.6, 129.4, 129.1, 128.4, 123.8, 57.8, 54.5, 21.1. Anal. Calcd:
C, 62.33; H, 5.67; N, 18.17. Found: C, 62.49; H, 5.98; N, 18.23.
IR: 3130 cm-1 (C-H in triazole).
Sun and Wu
SCHEME 1: Designed Ligand-Accelerated
Cu(I)-Catalyzed Azide-Alkyne Cycloaddition Reaction
For [azide]/[alkyne] ) 1/2 and 2/1, only the amount of alkyne
and azide was changed to 0.732 and 1.0 g, respectively, and
other reacting and measuring conditions were all the same.
2.4. Investigation Methods. 2.4.1. Principal Component
Analysis. After subtracting the solvent spectrum and baseline
correcting, all ATR-FTIR spectra at the 1:1 molar ratio of
reactants with an increment of 1 °C were used to perform
principal component analysis (PCA) calculation by the software
The Unscrambler ver. 9.7 (CAMO Software AS, 1986-2007).
The data set used for PCA was mean centered in advance.
2.4.2. Two-Dimensional Correlation Spectroscopy. PCAreconstructed ATR-FTIR spectra at the time range of 0-40 min
were used to perform 2D correlation analysis. The 2D correlation
analysis was carried out using the software 2D Shige ver. 1.3
(Shigeaki Morita, Kwansei-Gakuin University, Japan, 2004-2005)
and was further plotted into the contour maps by Origin program
ver. 8.0. In the contour maps, warm colors (red and yellow)
are defined as positive intensities, while cool colors (blue) are
negative ones.
3. Results and Discussion
The designed ligand-accelerated CuAAC reaction (Scheme
1) was real time monitored by a Mettler-Toledo ReactIR
instrument equipped with a silicon ATR probe (Figure 1). The
solvent (DMF) spectrum has been subtracted to enhance the
signal of reaction species. Four regions were the focus in this
paper: region 3300-3010 cm-1, where C-H stretching vibrations in alkynyl and 1,2,3-triazole locate; region 2200-2020
cm-1, where the stretching vibration of -N-NtN in azido
locates; region 1780-1715 cm-1, where CdO stretching
vibration locates; and the fingerprint region 1400-900 cm-1.
To further investigate the effect of reactant concentration on
the reaction dynamics, another two experiments with excess
alkyne and azide were also performed.
From Figure 1c-h, the decreasing of characteristic peaks at
3224 and 2098 cm-1 of alkyne and azide and the increasing of
the characteristic peak at 3139 cm-1 of 1,2,3-triazole can be
easily observed. We plotted absorbance-time curves (Figure
1i-k) and found that the two reactants both showed a linear
decrease of concentration (represented by absorbance) at the
beginning of the reaction and a gradually decreasing consuming
rate after a period of time, while the product or 1,2,3-triazole
exhibited an “S-shaped” increase. Similar discontinuous kinetic
profile has also been observed by Nishimura et al.,14 who
attributed it to the result of the formation of tristriazole. Judging
from the slopes of the two reactants, we concluded that alkyne
always had a slightly higher consuming rate than azide, no
matter what the molar ratio was. Furthermore, under conditions
of little Cu(I) (1/50 of reactants), a deviation from 1:1 ratio of
reactants would induce the decrease of reacting rate, indicating
Cu(I)-Catalyzed Azide-Alkyne “Click” Cycloaddition
J. Phys. Chem. A, Vol. 114, No. 32, 2010 8333
Figure 1. Time-resolved online IR spectra at different molar ratios of reactants (rt ) 20 °C): (a-d) [azide]/[alkyne] ) 1/1; (e,f) [azide]/[alkyne]
) 1/2; (g,h) [azide]/[alkyne] ) 2/1. The absorbance (normalized)-time curves were also plotted in i, j, and k, respectively.
that azide and alkyne may form a 1:1 complex in the reacting
process. The formation of azide-alkyne 1:1 complex can also
be supported by their same changing reaction rate orders roughly
determined by ln(-dA/dt)-lnA scatter plots (as for 1:1 molar
ratio, alkyne, 0 f 0.62; azide, 0 f 0.59; see Supporting
Information for details). It is in good conformity with the
stepwise mechanism proposed by Sharpless et al. In addition,
excess alkyne would lead to longer period of linearly consuming
tendency of the two reactants, indicating that the complexation
of alkyne and azide was mainly controlled by the concentration
of alkyne. This also supports the current mechanism in which
alkyne would first coordinate with Cu(I) before the formation
of 1:1 complex with azide. As the product (1,2,3-triazole) with
S-shaped increasing had an accelerating process at the beginning
of the reaction, we can primarily deduce the sequence of
different reacting species as follows (f means prior to or earlier
than): consumption of alkyne f consumption of azide f
formation of 1,2,3-triazole.
The fingerprint region 1400-900 cm-1 (Figure 1a) is rather
complicated and hard to analyze. However, this region contains
much more spectral information about subtle structural changes,
which is very suitable for chemometrics analysis. Principal
component analysis (PCA) was employed in this paper. Interestingly, there are only two principal components generated here,
wherein the first principal component (PC-1) can explain 75%
of spectra variation, while the second principal component (PC2) can explain 23% of spectra variation.
From the loadings plots of these two components in Figure
2c,d, we can determine that PC-1 should arise from the
contribution of the product 1,2,3-triazole and PC-2 from the
combining contributions of the two reactants. It should be noted
that PCA always undergoes a mean-centered pretreatment, and
only if two components have a strict stoichiometric relationship
or linear functional relationship, there would be only one
component left because it is necessary to describe all of the
spectral variation with one component. The number of components calculated from PCA revealed that CuAAC reaction is a
strict stoichiometric reaction, and the spectral combination of
the two reactants indicates that azide and alkyne should have
formed a 1:1 complex, which accounted for the second principal
contribution to spectral variation. However, considering there
is no obvious deviation of spectral changes of azido and alkynyl
stretching vibrations and no new bands formed at any time
points (Figure 1), we contributed this 1:1 complex to the slightly
complexing intermediate (6 in Scheme 2).
The score changes of PC-1 in Figure 2a is easy to understand,
similar to the characteristic peak intensity variation of 1,2,3triazole in Figure 1i. However, the score changes of PC-2
underwent mainly three stages, which can be easily observed
in the scatter plot in Figure 2b. Before 11 min, PC-2 or the
intermediate (1:1 complex) and PC-1 or 1,2,3-triazole gradually
formed. At 12-29 min, the concentration of PC-2 or the
intermediate is nearly unchanged, while the formation of PC-1
or 1,2,3-triazole reached the maximum. In other words, at this
stage, the consumption of alkyne and azide and the formation
of 1,2,3-triazole approached a balance. At the last stage between
30 and 40 min, alkyne and azide had been totally consumed,
and then the intermediate was largely consumed causing obvious
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J. Phys. Chem. A, Vol. 114, No. 32, 2010
Sun and Wu
Figure 2. (a) Scores plot and (b) scatter scores plot of the first two principal components calculated from PCA on mean-centered online IR spectra
with 1:1 molar ratio of azide and alkyne; (c) spectra comparison between loading plots of PC-1 and IR spectrum of pure triazole as well as (d)
between PC-2 and pure azide and alkyne derived from experimental purification. The first two principal components explain 98% of the variation.
SCHEME 2: Modified Catalytic Cycle for Cu(I)-Catalyzed Azide-Alkyne Cycloaddition Reaction According to Infrared
Correlation Analysis Results
score changes, while the formation of PC-1 or 1,2,3-triazole
slowed. On the basis of the above analysis, we can easily
confirm the rate-determining step to be the transition of the
intermediate 1:1 complex of two reactants to the product 1,2,3triazole.
To further examine the variation sequence of all reacting
species, the three spectral regions in Figure 1b-d were all used
to perform 2D correlation analysis, as shown in Figure 3.
Synchronous spectra reflect simultaneous changes between two
given wavenumbers. From Figure 3a, we can see an obvious
band splitting of CdO at 1763 and 1736 cm-1, which was
contributed from the reactant alkyne and the product 1,2,3triazole, respectively. Interestingly, asynchronous spectra had
distinguished the azido stretching vibration to three peaks at
2125, 2098, and 2079 cm-1. Because an obvious shoulder peak
can also be found in the IR spectrum of pure azide without
Cu(I) (see Supporting Information for spectral comparison), we
are inclined to assign these two peaks at 2125 and 2079 cm-1
to the two asymmetric NdN stretching vibrations of the azido
resonance structure -NdN+dN- and the peak at 2098 cm-1
to the single asymmetric NtN stretching vibration of the other
azido resonance structure -N--N+tN. Additionally, C-H
stretching of alkyne exhibited two splitting bands at 3224 and
3182 cm-1, which can be assigned to free tC-H and tC-H
coordinated with Cu(I), respectively.
Cu(I)-Catalyzed Azide-Alkyne “Click” Cycloaddition
J. Phys. Chem. A, Vol. 114, No. 32, 2010 8335
Figure 3. Two-dimensional (a) synchronous and (b) asynchronous spectra of the three spectra regions (3300-3010, 2200-2020, and 1780-1715
cm-1) generated from online IR spectra with 1:1 molar ratio of azide and alkyne in the period of 0-30 min. Warm colors (red and yellow) are
defined as positive intensities, while cool colors (blue) are negative ones.
The sequence can be determined according to Noda’s rule,13
which can be summarized as follows: if the cross-peaks (V1, V2,
and assume V1 > V2) in synchronous and asynchronous spectra
have the same sign, the change at V1 may occur prior to that of
V2, and vice versa. The operation details for determination of
sequence order according to a simplified method15 can also be
found in Supporting Information, and only the final specific
orders are presented here for all reacting species in the CuAAC
reaction (f means prior to or earlier than): 3182 f 3224, 1763
f 2125, 2079 f 2098 f 3086 f 3139 f 3032 f 1736 cm-1,
e.g., tC-H (coordinated with Cu(I)) f tC-H (free), CdO
(alkyne) f -NdN+dN- f -NdN+dN- f phenyl f C-H
(triazole) f CdO (triazole). From the sequence derived from
2Dcos, we can clearly find that the consumption of alkyne is
earlier than azide followed by the formation of the product 1,2,3triazole, which is consistent with our previous analysis.
For the convenience of description, the sequence has been
presented in Scheme 2, in which some modifications on the
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J. Phys. Chem. A, Vol. 114, No. 32, 2010
basis of the catalytic cycle proposed by Sharpless have been
made, wherein it is noted that the consumption of Cu(I)coordinated alkyne 2 was earlier than that of free alkyne 1,
contrary to the reacting direction. That is because the coordination of Cu(I) and alkyne to afford Cu(I) acetylide 3 proceeded
very fast and 2Dcos cannot discern this sequence. The sequence
between the two azido resonance structures of -NdN+dN- 5
and NdN+dN- 4 is also very meaningful in that it was the
resonance structure -NdN+dN- 5 that participates in the
complexation between azide and alkyne. It is presumed that
the coordination of Cu(I) acetylide to 5 may lead to a relatively
lower activation energy in the following rate-determining step
from the perspective of charge distribution. Along with the
formation of 1,2,3-triazole 8, phenyl and CdO were affected
successively, with CdO being the slowest response. According
to the catalytic cycle proposed by Sharpless, the azide-alkyne
1:1 complex 6 would first produce a preproduct or triazolylcopper derivative 7 followed by its proteolysis to afford 1,2,3triazole 8. The slowest response of CdO in triazole indicates
that this proteolysis process was also very fast and 2Dcos cannot
discern it. Thus, the rate-determining step can be easily
confirmed only to the transition of azide-alkyne 1:1 complex
6 to the preproduct 7. This is the first experimental proof for
the rate-determining step of the CuAAC reaction. In Scheme
2, the structure of azide-alkyne 1:1 complex 6 has also been
presented according to a previous report.6a
4. Conclusion
A designed ligand-accelerated CuAAC reaction was monitored for the first time by real time infrared analysis technique
based on ATR-FTIR principles. Three reacting groups directly
participating in the reaction (azido, alkynyl, and 1,2,3-triazole)
are all IR-responsive and can be traced primely. The absorbancetime curves with different molar ratios of reactants as well as
PCA calculations on the fingerprint region showed that the
consumption of alkyne and azide took place successively
followed by the formation of the product 1,2,3-triazole, and a
1:1 complex of two reactants or the intermediate would be
formed in the reaction process, in good conformity with current
catalytic mechanism that Sharpless proposed. 2Dcos discerned
the sequence of all the reacting species and confirmed the ratedetermining step of CuAAC reaction to be the transition of the
azide-alkyne 1:1 complex to the preproduct 1,2,3-triazole. A
modified catalytic cycle has also been plotted to get a better
understanding of the CuAAC reaction.
Sun and Wu
Acknowledgment. We gratefully acknowledge the financial
support National Science Foundation of China (NSFC) (20934002,
20774022), the National Basic Research Program of China (Nos.
2005CB623800, 2009CB930000).
Supporting Information Available: Determination of rate
orders, operation details of sequence order determination from
2Dcos results, spectral comparison of azido vibrations. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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